Method and device for transferring a substance between closed systems

ABSTRACT

The invention relates to a method and to a device for transferring a substance between closed systems (G 1  G/Z, Z, G+G/Z), which prior to the transfer are connected in a sterile manner and can be disconnected from each other in a sterile manner, and wherein means for transferring the substance are provided. The goal is to enable a contamination-free transfer of the substance without gas inclusions between closed systems. This is achieved with respect to the method in that the pressure differences occurring during the transfer of the substance are compensated for within the system. This is achieved with respect to the device in that a pressure compensating unit ( 1 ) is provided, which has a sterile flow connection to at least one system (G, G/Z, Z, G+G/Z).

The invention concerns a method for transfer of a substance betweenclosed systems, in which the closed systems, namely at least one sourcesystem and at least one target system are at least simply connected insterile fashion before transfer, in which case the substance enters thetarget system and, after transfer of the substance, the target systemand the source system can be separated from each other in sterilefashion.

The present invention also concerns a device for transfer of a substancebetween closed systems, especially for performance of the method inwhich the systems can be connected in sterile fashion to each other andcan be separated in sterile fashion from each other and have means totransfer the substance.

Operating free of contamination in closed systems under conditions ofcleanroom technology is known per se in many areas of technology,especially medical technology. A system is considered closed, if it atleast cannot exchange matter with the surroundings.

There is often the requirement precisely in medical technology tointroduce matter into the closed system so that any contamination isruled out and processing or investigation can occur there. This includesfor example preparations of cell populations, their cryopreservation andremoval of samples for laboratory studies from these preparations, whileguaranteeing a closed state of the system.

Sterile connection techniques like “sterile docking” and “sterilewelding” are already known from the U.S. Pat. No. 6,022,344 with whichthermoplastic tubes of two closed systems could be connected in sterilefashion to each other and also separated in sterile fashion again.“DOCKING” involves the making of cuts under the influence of temperatureand direct sealing of both ends of two plastic tubes. “WELDING” involvesseparation of the connection with compression under temperature to forma homogeneous cross-sectional surface and cutting so that two closedinterfaces are formed. Sterile connection, however, can also be producedindependently of the aforementioned connection techniques, like steriledocking and sterile welding by mounting and sealing plastic vessels andtubes under cleanroom conditions and sterilization measures in knownfashion.

Removal of substance under a sterile bench in the clean room by means ofsyringes is also known from practice, which has shortcomings because aclosed state of the system is abandoned.

A specific application from matter or substance that is to be introducedto the closed system pertains to stem cells, which are recovered frompatient blood during apheresis treatment. Before a cancer patient issubjected to chemotherapy, stem cells are taken from him. Only then doesthe patient receive chemotherapy. Since stem cells are broken downduring this chemotherapy, the removed stem cells are later supplied tothe patient.

Apheresis treatment proceeds by taking blood from the patient andtransferring it in a closed system. Centrifugal forces act in the closedsystem during which the blood is broken down into components. Cellpopulations that contain stem cells are separated to initially securethem. The remaining blood is returned directly to the patient. Theseparated cell populations, depending on their purpose, are providedwith additives, for example, for the patient's own plasma and foreignplasma.

This substance present as a cell suspension must be made storable inorder to be later supplied to the patient. Making it storable can onlyoccur using the chemical compound dimethyl sulfoxide, subsequentlycalled DMSO, in a freezing bag for cryopreservation. The chemicalcompound DMSO serves to concentrate the cell fluid in the preparation inorder to compensate for differences there between different osmoticpressures. The stem cell substance is protected fromdestruction/bursting of the cells by this. The freezing bag consists ofethylene vinyl acetate, a plastic which is also abbreviated EVA.

While the stem cell preparation can be further treated under sterileconditions, addition of the chemical compound DMSO represents the weaklink with respect to maintaining a closed system. Even addition of DMSOthrough a filter, as is known from DE 101 24 487 A, cannot preventcontaminants, like viruses or toxic gases, from entering the closedsystem. Because of its aggressiveness relative to plastics DMSO alsocannot be positioned in the bag system by the producer and subjectedthere to sterilizing pretreatment. Storage of the chemical compound DMSOin any case must be conducted over the long term in chemically inertvessels, for example, made of borosilicate glass with asolvent-resistant closure.

DE 101 51 343 A1 deals with a bag system for cryopreservation of bodyfluids. There the substance is transferred to another closed system froma glass ampule, which is situated within a closed system. Transferoccurs via a sterile connection, which is accomplished before transferduring production of a closed system. After transfer, sterile separationoccurs with disposal of the emptied source systems filled beforehandunder sterile conditions. A shortcoming in this bag system with respectto transfer is that volume-precise metering is not possible and airinclusions cannot be avoided in defined fashion within the substancebeing transferred but depend on the skill of the person handling theflexible bag. Air inclusions in the substance cannot be ruled out andcan adversely influence the effects and results of later applications,for example, mixing processes. Continuity of transfer is also notguaranteed. A further shortcoming is that the only solution tocompensate pressure differences in the system is seen in releasingexcess air via filters into the surroundings. As already stated inconjunction with DE 101 24 487 A1, however, even a filter cannot preventcontaminants like viruses or toxic gases from entering the closedsystem.

Starting from the already known prior art the underlying task of theinvention is to provide a method and device in which contamination-freetransfer of the substance is made possible without gas inclusionsbetween closed systems.

The aforementioned task is solved with reference to the method by thefeatures of claim 1. The method of the type in question is characterizedby the fact that pressure differences occurring during transfer of thesubstance are compensated within the system.

The aforementioned task is solved with respect to the device by thefeatures of claim 8. A device of the type in question is characterizedby the fact that a pressure compensation device is provided which is insterile flow connection with at least one system.

Starting from DE 101 51 343 A1, it was initially known relative to themethod that compensation of pressure differences there occurs bydischarging air from the bag system into the environment, in which caseit is tolerated that contaminated surrounding air enters the closedsystem, despite filters. It was recognized according to the inventionthat the sterility of the closed system need not be abandoned in any waywhen the pressure differences are compensated exclusively within thesystem. This finding is implemented by means of the device according tothe invention in that a pressure compensation device is provided whichis in sterile flow connection with at least one system. In other words:displaced air advantageously is not released to the surrounding air buttrapped in a pressure compensation device and available there inconjunction with substance removal processes so that no vacuum isformed. The device according to the invention can be used as adisposable article at the location of preparation, for example, in theblood bank or transplantation laboratory. Standardized industriallyproduced disposable articles according to the invention enormouslyexpand sterile work and widen the use possibility of substances.

Pressure compensation can occur anywhere volume changes of the substanceoccur. Generally this could occur both in the source system and in thetarget system. In one application in which the source system consistsmerely of a sterile, sheathed ampule with transfer device that can beconnected in sterile fashion, pressure compensation could also be fullyswitched to the target system and the partial vacuum developing in thesource system tolerated, since the empty ampule after sterile separationfrom the target system is disposed of.

Implementation of volume-precise transfer of the substance is ofessential importance to the invention, since this achieves a situationin which the substance is transferred in metered fashion. This includessemiquantitative metering processes or metering with calibrated meteringdevices.

In principle, the substance could be actively transferred from thesource system to the target system or actively removed from the sourcesystem. With respect to desired metering, calibrated syringes orcarpules could then be used. As an alternative, the substance couldreach the target system under the influence of gravity. Metering couldoccur here via a calibrated drip chamber. Transfer devices, likesyringes, carpules, drip chambers, could in turn form closed systems orbe components of closed systems.

In implementation of the method the source system could be connected toseveral different target systems. Multiple connection of the sourcesystem to one or more target systems could be possible in succession orsimultaneously. Partial amount transfer of the substance is madepossible by this.

During the method it could happen that the target system becomes thesource system when the received substance is conveyed to another targetsystem. This could either happen after a first sterile connection andseparation or the device is set up so that a function change occurs byopening and closing of metering valves. A metering valve between thesource and target system initially opened to receive the substance isclosed after filling of the target system. If substance is transferredto another target system from the filled target system by openinganother metering valve, the filled target system now has a sourcefunction.

In a source system that is marketed in the form of a blister package andthen directly available for use the substance could preferably beintroduced under sterile conditions to the source system under cleanroomconditions, which is then closed in sterile fashion to form a blisterpackage. In a simple practical example a container could be filled inthe plant under cleanroom conditions and closed, then go to thelaboratory physician who produces sterile connection to a target systemand can thus transfer the prepared substance. A differently configuredbut likewise simple practical example proposes to produce a container atthe plant without substance, which contain means to transfer thesubstance—here to remove it from a source system available in thelaboratory or delivered at the same time.

According to a preferred variant of the device according to theinvention, the closed system, which can be a source system, a targetsystem or also a system with source and target function, could have acontainer for the substance. The container separates the surroundingsfrom the internal space of the closed system in which the substancecould already be contained. The pressure compensation device could bebonded to the container and be present as a rubber bag. The connector ofthe pressure compensation device could be welded into the container sothat the closed state of the system is not interrupted. As analternative, the pressure compensation device could also be an integralcomponent of the container via a special shaping method.

The means for transfer of the substance could include at least oneconnector for sterile connection to at least one connection of anotherclosed system. The connector could be designed as a thermoplastic tube.Like the pressure compensation device, the connector to the container ofthe system could also be bonded in sterile fashion. The connector orplastic tube could have a length that permits repeated sterileconnection and separation. Going further, several connectors or plastictubes could be provided for multiple connection to another closed systemor several other closed systems.

In terms of design, the container of a device according to the inventioncould include a base plate. This base plate could consist of a rigidplastic and have holding devices and/or connection sites that concernthe connection. In order for the objects contained in the container tobe examinable, the container could be transparent at least in theflexible areas of the wall. Transparency, for example, permits meteredsubstance removal or filling and in a special practical examplepositioning or mounting of the transfer device within the container.Otherwise, at least a view of the amount of substance available isfurnished by transparency. In addition, the container could also have acover plate. The flexible wall, especially the bellows, or also anenclosure could extend between the cover plate and base plate. Astabilization element could be arranged on the bottom of the coverplate, which contributes to fastening of a receptacle for the substancearranged within the container during transport. The holding devicescould be assigned to the base plate and/or cover plate and also have thefunction of spacers or stabilizers in addition to the holding function.

A particularly easy-to-handle variant of the at least partially flexiblecontainer consists of designing the flexible wall in the form of abellows. This bellows could be strongly deformed in all directions basedon an extremely tear-proof thin material, which could also bestretchable. This deformation is reversible. Because of the limitedmaterial thickness objects situated in the interior of the containercould be grasped, joined to each other or positioned or otherwisemanipulated. For the gripping movement it is particularly important thatthe wall include at least two opposite flexible areas. With respect toproduction of the container the bellows could be welded or glued insealed fashion to the base plate and cover plate.

A further variant of the device according to the invention proposessterile connection of the closed systems already at the plant. Inparticular, this concerns the combination of a source system and asource and target system into an overall system. Specifically, thesource system could be connected in sterile fashion to a closed sourceand target system in the sense of a metering device and form an overallsystem. It is understood that an overall system can also contain morethan two closed systems. The possibility exists after emptying of thesource system to separate this in sterile fashion and dispose of it orto use it elsewhere for partial amount removal. Successive separationcan occur in any system with a source function, if the previous sourcesystem is completely emptied or emptied as desired.

Gravity-operated devices according to the invention without meteringfunction are generally pure source systems. The substance is transferredto the other closed system from the source system under the influence ofgravity. The source system could then have a container in which thesubstance is contained and whose connection in the operating positionpoints toward the floor.

According to a first very simple practical example of the deviceaccording to the invention the container itself could form thereceptacle for the substance and be present, for example, as acollapsible, flexible bag. This practical example permits cost-effectiveproduction and storage of substances, like preparation solutions, at thelocation of use, while maintaining a closed condition of the systems.

In the first practical example the connection could open into thecontainer, on the one hand, especially extend minimally into thesubstance and be provided there with a reclosable closure. On the otherhand, the connection could emerge from the container and be welded withits free end in sterile fashion to the other system or already bewelded.

Reclosability of the end of the connection extending into the substancepermits partial removal of substances, like preparation solutions,naturally heeding sterile connection and disconnection. Formation of theclosure as a snap closure made of sealing material, which is equippedwith fastening bridges and can be operated through the flexible wall ofthe container, is of special significance for the first practicalexample. The fastening bridge serves for nonclosability of the closure.The closure ensures that the substance does not reach the connectionbefore sterile connection has occurred and is possibly contaminated. Thematerial of the container present as a bag is soft, but strong enoughnot to be damaged during manipulation of the closure.

In terms of design, the container could also include in its bag form abase plate through which the connection is passed through in sealedfashion. A pressure compensation device can be arranged so that it opensinto the area of the container filled with air or inert gas, whichalways points up in the operating position.

According to the simple and particularly cost-effective modification ofthe first practical example of the device according to the invention, ametering valve that could be advantageously operated from the outsidecould be provided so that at least estimated partial amounts can beremoved.

A variant of the first practical example suitable for volume-precisetransfer consists of the fact that the source system present there as abag is already connected in a sterile fashion at the plant to asource/target system in the form of a calibrated drip chamber and formsan overall system. In this way the metering device is contained in theoverall system as an intrinsic closed system which is alsogravity-operated. Here again a metering valve can be assigned to thesource system. An overall system that also contains additional closedsystems in addition to the source system and the metering device withcombined source and target function is also conceivable. In each case,however, sterile connection at the plant between the systems applies ineach case as a method step prior to substance transfer.

The container in larger package sizes could have a volume between 30 mLand 1000 mL. With small amounts so-called “minibags” reach a volumebetween 10 mL and 30 mL. These “minibags” are prescribed for individualuse and can each contain the maximum required amount of substance forthe intended preparation.

A special second practical example of the device according to theinvention consists of the fact that it is formed as a gravity-operatedmetering device. For this purpose at least two connections can beprovided for the system, which include an inlet and an outlet pointingtoward the floor in the operating position. A calibrated drip chambercan be provided as container of the system, in which the substance is atleast temporarily contained. The substance is fed via the inlet from asource system and discharge through the outlet to a target system. Ametering valve can be assigned to the inlet and/or outlet. For theclosed condition of the system it is important that the inlet and outletare arranged sealed on the drip chamber. For example, the drip chambercould include a base plate, cover plate and transparent plastic jacketbetween the cover and base plate. With this container design theconnector of the pressure compensation device, especially via the coverplate, could open in sealed fashion into the drip chamber.

The calibrated drip chamber with the two connectors that can beconnected in sterile fashion in the second practical example forms aclosed system in the sense of the gravity-operated metering device,which is both a source and target system. The thing to do is have thesource system for the aforementioned gravity-operated metering devicealso release the substance by gravity into the calibrated drip chamberafter sterile connection of the connectors. The amount of substancearriving from the source system could be regulated via the meteringvalve with the inlet.

A third practical example of the device according to the invention,which is also based on the gravity principle, proposes to arrange areceptacle in the form of a bottle or ampule in the container of thesource system, within which the substance is situated and whose closurepoints toward the floor in the operating position. According to apreferred design the receptacle could be fastened to a cover plate inthe container. An eye could be provided on the outside of the coverplate so the container can be suspended like a drop. The connector couldbe welded into the base plate opposite the cover plate.

In the third practical example in question the means for transfer of thesubstance could include a short cannula for outlet of the substance,especially a liquid, and a long cannula for air or inert gas supply. Thecannulas could puncture the closure of a receptacle in the operatingposition and extend into the receptacle.

In a simple variant of the third practical example only the shortcannula could be in a flow connection with the sterile-connectableconnector in the operating position. A connection piece connected to theshort cannula could then extend in the form of a plastic tube into aplastic tube of the connector that is larger in terms of cross section.The connector is welded onto the base plate of the container and plastictube connected to the short cannula passes through a passage opening inthe base plate in sealed fashion. The long cannula opens into thecontainer equipped with a bellows to which the pressure compensationdevice is connected. In the rest position a bellows is deployed andaccommodates the two cannulas. The cannulas are prevented frompuncturing the closure of the receptacle by a holding device. Theshaping of the receptacle can be utilized to fix the holding device andthe holding device can also be supported on the base plate. The holdingdevice according to a preferred design variant that is particularly easyto handle could be present in the form of a flexible slit sleeve. Aslong as the cannulas are not in use, they are arranged in the holdingdevice which protects the flexible wall of the container, bellows frompuncturing. The sleeve is supported in the rest state, on the one hand,against the base plate of the container and on the other hand againstthe shoulders of the receptacle. In the operating position the sleeve ismanipulated from the outside via the bellows, positioned around theampule barrel and the cannulas puncture the closure. The bellows of thecontainer is then collapsed.

In this variant the volume of the receptacle could be predetermined sothat the removed amount can be estimated. The arrangement of a meteringvalve on a connection improves volume- and time-precise metering of theamount intended for the other closed system.

A somewhat more demanding variant of the third practical example withmore precise metering capability proposes that the container include acalibrated drip chamber. This drip chamber could be directly welded tothe base plate of the container and with appropriate sealing andsterility of all connectors and connection pieces be a component of thesource system. Both cannulas (both long and short cannulas) are in flowconnection with the drip chamber via connection pieces. The shortcannula within the container could be assigned a metering valve whichcan be operated via the bellows of the container. The connector forconnection to another system can start from the calibrated drip chamber,which expediently points toward the floor in the operating position.

As an alternative to a welded-on drip chamber, however, an overallsystem prepared sterile at the plant could also be formed, consisting ofa source system and metering device in the sense of a combination of asource and target system. The large cannula could then also opendirectly into the pressure compensation device. In this alternative onlyone pressure compensation device is advantageously provided, whichensures pressure compensation in the container and in the receptacle ofthe source system, as well as in the calibrated drip chamber of thetarget and source system—in short, in all components of the closedoverall system.

Finally, there is also the possibility of connecting the connector ofthe source system according to the third practical example subsequentlyin sterile fashion to a gravity-operated metering device according tothe second practical example. Here again the source system could beassigned a metering valve.

As an alternative to a gravity-operated device according to theinvention according to the first three practical examples, the fourthpractical example deals with a variety of uses of a calibrated syringewith an ampule plunger and ampule barrel as means for active meteredtransfer of the substance.

Force application can occur manually by the user. However, the syringecan also be introduced into an electric motor pump system known per se,in which metering can be programmed precisely in terms of time andvolume.

On the one hand, the syringe could be filled within a container from areceptacle containing the substance or on the other hand the ampulebarrel of the syringe could already be filled with substance or finallybe filled by filling the syringe with substance from another sourcesystem. The ampule barrel of the syringe simultaneously forms agenerally temporary receptacle for the substance, since transfer occursvia the syringe. The syringe could be operated from the outside via theat least partially flexible wall of the container, especially via itsbellows.

The system including the syringe could have superimposed source andtarget function, if filling with substance and delivery of substanceoccur in the same system.

According to one variant of the fourth practical example the syringecould be arranged within the container and be operable from the outsidevia an at least partially flexible wall of the container, especially viaits bellows. In addition to the syringe, a cannula could also becontained, which can also be handled via the bellows. The syringe wouldbe initially packed with the cannula. The stopper of the receptaclewould then be punctured and the syringe filled, i.e., filled withsubstance within the system. The cannula would then be removed and thefilled syringe connected to the connector oriented toward the targetsystem with a connection piece in the form of a tubular connector.Finally, the ampule plunger would be forced into the ampule barrel sothat the substance flows into the connector and into the target systemconnected in sterile fashion.

The connection piece could also be present in the form of an internalline. The internal line in the rest state could extend through a passageopening of the container into the connector and be wound in a spiralwithin the container. The internal line then initially extends into theplastic tube only far enough so that it can be connected withouthindrance to the connector of the other closed system. The internal linecould have a smaller cross section than the connection with a plastictube of the connection leading to the other closed system and consist ofa rigid, flexible material with a sliding surface. Polypropylene, forexample, could be considered as material. The free end of the internalline extending into the container could be connected to the syringe inorder to be operated.

This variant with internal line permits precise positioning of the freeend of the internal line in the other system and can serve both todeliver the substance and to receive the substance. Advance of theinternal line through the connector connected in sterile fashion to aspecific withdrawal site in the other closed system could beaccomplished via the flexible wall of the container. In the case ofsubstance removal the removed substance could be blood or umbilical cordsamples that are to be furnished to the laboratory. The status of thepreparation and its compatibility for the patient must be determined inthe laboratory. Via the syringe on the internal line the sample isremoved from the other system and introduced in the first sterile systemto the receptacle, here via the suction and ejection movements of thesyringe through a cannula and the stopper of a preferably evacuatedampule. After “retrieval” of the internal line via the bellows into thefirst system, separation of the withdrawal system can be carried out.During transfer of a substance situated in the receptacle of thecontainer into the other closed system the connection between thesyringe and cannula is initially produced, the substance taken up withit, the cannula then removed and the syringe connected to the internalline, whose free end was already positioned in the target system. Thesubstance is conveyed through the internal line to the destination withthe plunger movement. After transfer, the internal line is retractedinto the first system via the connected plastic tubes of both systemsand the systems are separated in sterile fashion.

As already mentioned, the ampule barrel of a syringe according toanother modification of the first practical example of the deviceaccording to the invention could simultaneously form the receptacle forthe substance, the ampule barrel according to another variant of thefourth practical example could then be positioned in a holding device onthe base plate and have a connection in the form of a plastic tube,which passes through the base plate in sealed fashion and serves forsterile connection to another system. The ampule barrel could already befilled in advance with the substance in this case.

Another modification of the fourth practical example of the deviceaccording to the invention proposes to provide the ampule barrel with acannula with a cannula closure, which can be opened and closed via theflexible wall of the container. More rapid emptying and filling of thepressure compensation device is achieved according to the variable gasvolume in the container, if the container includes two chambers with twoconnection pieces for preferably one pressure compensation device oralso two smaller separate pressure compensation devices. The firstchamber could then contain the ampule plunger and the second chambercould contain the ampule barrel with the cannula and the closure.Deviating from other practical examples in which the connector is weldedinto a base plate, here the second chamber of the container could itselfform the connector for sterile connection to the connector of anotherclosed system on the end facing away from the first chamber for theampule plunger.

The other closed system, here the source system, could be present in thepractical example in question in the form of an ampule containing thesubstance. This ampule could in turn have a plastic enclosure with aconnector for sterile connection of the connection of the container orsecond chamber, in short the connector of the first closed system. Theenclosed ampule with a connector connectable in sterile fashion initself forms a closed system and with respect to aggressive substancescould consist of borosilicate glass and be equipped with an elastomerpuncture stopper. Finally, the cannula of the device according to theinvention is moved through the connections to the ampule, the ampuleplunger is forced into the ampule barrel and air or inert gas isinjected into the ampule after puncturing of the elastomer stopper. Theampule contents are then under pressure and fine metering is thenpossible during removal of the substance. The ampule plunger is nowwithdrawn from the ampule barrel during drawing in of the substance andthe two systems are separated in sterile fashion. The now filled closedsystem is available as source system for sterile connection again to atarget system.

In another variant of the fourth practical example the ampule plungerand the ampule barrel could be in a flow connection. The ampule barrelcan have a connector that can be connected in sterile fashion to anotherclosed source system. In addition, a metering valve could be provided.The connector could be present as a plastic tube that extends into theampule plunger. The ampule barrel could have a connection that can beconnected in sterile fashion in a closed target system away from theampule plunger, which is also provided with a metering valve.

To draw in substance from the source system the connection of the ampulebarrel is closed, that of the ampule plunger opened and the latter movedout of the ampule barrel. The substance then flows from the sourcesystem into the target system, which is represented in this situation bythe syringe. To convey the drawn-in substance to the target system, themetering valve is closed on the side of the ampule plunger and opened onthe side of the ampule barrel. The ampule plunger is introduced to theampule barrel and the substance thus transferred to the target system.In this situation the syringe is the source system. Another advantageousapplication is obtained, if the ampule barrel is from both directions tothe mixing container or target system. This can be done, if fillingoccurs only partially via the ampule plunger, i.e., the ampule plungeris not placed in the maximum introduction position. If the meteringvalve on the side of the ampule plunger is then closed and the meteringvalve on the side of the ampule barrel opened and the now only halfintroduced ampule plunger withdrawn, suction of substance occurs fromthe source system connected in a sterile fashion on the side of theampule barrel. Two different substances are then situatedproportionately in the syringe, which were transferred in sterilefashion from both directions and can then be introduced to anothertarget system as a mixture. The device according to the invention justdescribed represents a particularly elegant solution for laboratorywork, which gets by without additional mixing containers on thisaccount.

A special advantage in this variant of the fourth practical example isalso the space-saving design of the container, which consists of acombination of an enclosure in the area of the ampule barrel and abellows in the area of the ampule plunger. The device according to theinvention because of this can be tightened better in a known syringepump, since the container is reduced to a minimum. Advance of thesubstance is continuously guaranteed by the alternation of suction andejection. The effective connection of the syringe to a syringe pumpmakes it possible to accomplish transfer of substance automatically atpre-established times.

A modification of the variant of the fourth practical example justdescribed consists of the fact that an overall system is formed with asource system according to the second practical example. The sourcesystem here has a receptacle in the form of an ampule facing the floorwith its opening in the operating state. During filling of the ampuleplunger of the syringe, substance is drawn in from the source system andthe ampule barrel filled. The syringe is the target system here. Whensubstance is conveyed to another target system, the syringe is then thesource system. The overall system could already be produced at the plantand the source and combined source/target system could be connected insterile fashion via a connection piece that extends to the tip of theampule plunger.

The overall system could also be formed by the fact that two sourcesystems are connected to a syringe and substance is removed by means ofthe syringe, on the one hand, from a source system via the ampuleplunger and, on the other hand, substance is removed from the othersource system via the ampule barrel. Mixing could then occur in thesyringe and the new substance could be transferred to another targetsystem after sterile separation and reconnection.

Regardless of how the syringe is accommodated in the container in theclosed system, the syringe together with the container could beincorporated in an ordinary syringe pump. Transfer of substance cantherefore be accomplished automatically at pre-established times.

Another variant of the fourth practical example proposes the syringeagain as mixing vessel. Substances are drawn into the ampule barrel fromclosed source systems via a multipath closure. This naturally does notoccur to complete filling of the ampule barrel. After the substances(for example, plasma and a mixture of white blood cells and plasma) haveentered the ampule barrel, this branch is closed and the branch thatconcerns introduction of DMSO is opened. Several DMSO-source systems canthen be coupled and contain rupture ampules within sterile containers.The DMSO branch is also closed and a third branch opened, via which anyair drawn into the system is released into the container that containsthe syringe. Finally the third branch (corresponding to the pressurecompensation device) is closed and a fourth branch of the multipathclosure opened, to which at least one freezing bag or also severalseries-connected and separately closable freezing bags are connected insterile fashion. The mixture is now ejected into the freezing bags bymeans of ampule plungers. The container in this variant is a foilenclosure dimensioned so that it has sufficient free volume for thesystem's gas/air. The generously dimensioned foil enclosure is providedhere with reference to the mixing syringe and DMSO rupture ampules whosefuture openings point downward. If the rupture ampules are broken,natural separation of liquid and gas occurs since the liquid flows tothe output of the container and any system gas/air rises upward into thefree space of the container. The question of incorrect mixing ofsubstances in system gas/air therefore does not come up in the containerfor the mixing syringe, since the gas, air escapes into the containervia the pressure compensation branch. The pressure compensation devicein this practical example is therefore not designed as a welded-on bag,but is achieved by dimensioning of the container and the arrangement ofthe substance outlet or via a branch of the pressure compensationopening into the container without adversely affecting the substance.

According to a fifth practical example the substance could be containedin a carpule or its carpule barrel, which is preferably calibrated.Carpule includes the carpule plunger movable in the carpule barrel. Asin a variant according to the fourth practical example, the thing to dohere is to construct the container from two chambers, one pressurecompensation device being provided per chamber. A cannula can beprovided in the first chamber, which faces the carpule barrel or itspuncture stopper with its tip and extends with its opposite end into theconnector. The connector could also be present here as a plastic tubethat can be connected in sterile fashion, which is to be connected in asterile fashion to the connector of another system, a target system.

The second chamber could consist of a cylindrical section and a bellows,in which case the carpule barrel is contained within a cylindricalsection as well as part of the carpule plunger and the rest of thecarpule plunger is contained within the bellows. This chamber and acoupling tube of the first chamber could be movable relative to eachother and preferably fastenable in a predetermined position to eachother with respect to performance of the puncture process. Transfer ofsubstance occurs after a flow connection is made to the connector inthat the carpule plunger displaces a sliding stopper within the carpulebarrel. The carpule according to the fifth practical example permitsbatchwise and volume-precise delivery of substance from the carpulebarrel of the first closed system into another closed system. The deviceaccording to the fifth practical example could be particularly useful asa disposable article.

A receptacle within a closed system, the source system, alreadycontaining a substance for transfer, is expediently closed after fillingin order to prevent emergence of substance within the container. Aclosure is naturally provided that is easy to open and also can beclosed. The closure in ampules, bottles or the carpule barrel could bein the form of a puncture stopper. The puncture stopper could consist ofelastomer and preferably be teflon-coated. As an alternative to areceptacle in the form of evacuated supply vessel with puncture stopper,commercial sample vessels closable airtight with a screw closure or snapclosure could also be used. Substance receptacles made of borosilicateglass are preferably used, which are suitable for aggressive substancesthat attack plastic. An aggressive substance could be, for example,dimethyl sulfoxide (DMSO), which is to be transferred into anothersystem that contains the stem cells of a patient for their storage. Thispractical example is especially significant with respect to storagestability of the substance DMSO of two years in the borosilicate glassreceptacle. A connection consisting of PVC is only briefly contactedduring transfer of DMSO so that the dissolution processes are not set inmotion. By sterile connection of the connections of both systems theDMSO enters the other closed system, which is present for example in theform of a freezing bag with a stem cell preparation. Apart from DMSO,another substance can also be contained in the receptacle which isincompatible with another component. Closed systems that are pure targetsystems could be tube and bag systems.

With respect to the fourth and fifth practical example the connector ofa system with source function could be connectable in sterile fashion toanother closed system, which contains an internal line. The internalline could be manipulated via the bellows of the container and permitsprecise positioning in another target system. The cross section of theinternal line is smaller than that of the connector of the source andtarget system.

With respect to the sterility of the device desired form the outset, itscomponents before connection could be arranged with the other closedsystem within a sterile package. A blister package is preferablyprepared. The package could also have a smooth surface without undercutsor recesses so that disinfection and introduction to the clean room isfacilitated. Disinfection could occur with 70% ethanol so that therequirements for introduction of the package into cleanroom areas aremet. Additional evacuation of the package is also possible. Pyrogenfreedom of the package could also be produced and it could begamma-sterilized.

A particular advantage of the device according to the invention lies inthe fact that inexpensive receptacles, like ampules, bottles, syringes,carpules and connections which are otherwise used in open systems can beapplied to fully closed systems. This is possible because thearrangement of the inexpensive source systems can occur in a closedsystem in a corresponding container or plastic enclosure, which caninteract with the other closed systems. Inexpensive source systems couldtherefore be used in a device according to the invention and madeaccessible to medical and scientific work. In principle, storage of anysubstance for complex preparation steps within a receptacle in a closedsystem is desirable.

There are different possibilities of configuring and modifying theinstructions of the present invention advantageously. For this purposethe patent claims, on the one hand, and the following application ofseveral practical examples in addition to variance of the device, on theother hand, are referred to by means of the drawing. In conjunction withthe explanation of the mentioned practical examples of the inventionpreferred embodiments and modifications of the instructions are alsogenerally explained. In the drawing

FIG. 1 schematically depicts a first practical example of the deviceaccording to the invention based on the gravity principle with acollapsible bag,

FIG. 2 schematically depicts the object from FIG. 1 combined withanother device according to the invention in the form of a calibrateddrip chamber to form an overall system,

FIG. 3 schematically depicts a variant of a second practical example ofthe device according to the invention in the form of a gravity-operatedmetering device,

i. in FIG. 3A a first variant of the device in a blister package,

ii. in FIG. 3B the object of FIG. 3A ready for operation,

iii. in FIG. 3C a schematic view of a second variant of the device withan inlet and several outlets,

iv. in FIG. 3D a schematic view of a third variant of the device withseveral inlets and an outlet,

v. in FIG. 3E a schematic view of a fourth variant of the device withseveral inlets and several outlets,

FIG. 4 schematically depicts a variant of a third practical example ofthe device according to the invention based on the gravity principlewith an ampule as receptacle,

FIG. 5 schematically depicts a variant of the third practical example ofthe device according to the invention based on the gravity principlewith a bottle as receptacle and with integrated drip chamber,

FIG. 6 depicts the object from FIG. 5 in a blister package,

FIG. 7 schematically depicts a variant of the third practical example ofthe device according to the invention with an overall system consistingof a source system and combined source/target system based on thegravity principle with an ampule as receptacle and with special holdingdevice

i. in FIG. 7A in the rest position and

ii. in FIG. 7B in the operating position,

FIG. 8 schematically depicts a variant of a fourth practical example ofthe device according to the invention with a syringe within thecontainer

i. in FIG. 8A in the rest position and

ii. in FIG. 8B in the operating position,

FIG. 9 schematically depicts a modification of the object in FIG. 8 withan internal line as connection piece,

FIG. 10 schematically depicts another variant of the fourth practicalexample of the device according to the invention with a syringe andholding device in the container,

FIG. 11 schematically depicts another variant of the fourth practicalexample of the device according to the invention with a syringe in atwo-chamber container,

i. in FIG. 11A the device in a blister package,

ii. in FIG. 11B the device during connection of the closed system to asource system,

iii. in FIG. 11C the device in the operating position—here puncturing ofan ampule of the source system,

iv. in FIG. 11D the device in the operating position—here emptying ofair in the ampule of the source system,

v. in FIG. 11E the device in the operating position—here suction ofsubstance from the ampule of the source system,

vi. in FIG. 11F the device in the operating position—here sterileseparation of the connector from the connector of the source system,

vii. in FIG. 11G the device in the rest position—readiness for transferof the substance removed from the source system into a target system,

FIG. 12 schematically depicts another variant of the fourth practicalexample of the device according to the invention with flow connectionbetween the ampule plunger and the ampule barrel of the syringe,

i. in FIG. 12A the device in the rest position, empty state of theampule barrel,

ii. in FIG. 12B the device during the suction process,

iii. in FIG. 12C the device at the end of the suction process, completefilling of the ampule barrel of the syringe,

iv. in FIG. 12D the device coupled to additional closed systems by meansof a system with internal line,

FIG. 13 schematically depicts the object from FIG. 12 as part of anoverall system combined with the source system from FIG. 7,

i. in FIG. 13A the device in the rest position, empty state of theampule barrel, cannulas outside of the ampule of the source system,

ii. in FIG. 13B device with prepared source system,

iii. in FIG. 13C the device during the suction process and

iv. in FIG. 13D the device during transfer of the substance into atarget system and

FIG. 14 schematically depicts a fifth practical example of the deviceaccording to the invention in the form of a carpule with a two-chambercontainer—here in the rest position.

FIGS. 1 to 14 show a device for transfer of the substance between closedsystems G, G/Z, Z, G+G/Z, in which the systems G, G/Z, Z, G+G/Z can beconnected to each other in sterile fashion and separated from each otherin external fashion and have means for transfer of the substance.

According to the invention a pressure compensation device 1 is provided,which is in sterile flow connection with at least one system G, G/Z, Z,G+G/Z. In the present five practical examples with all their variantsthe pressure compensation device 1 is bonded, namely welded to system G,G/Z, Z, G+G/Z.

The means to transfer substance includes at least one connector 2 forsterile connections with at least one additional system G, G/Z, Z,G+G/Z. Generally the connectors 2 are formed as thermoplastic tubes.

In all practical examples a container 3 is provided to form system G,G/Z, Z and the connector 2 is welded in sterile fashion to container 3of system G, G/Z, Z.

Depending on the variant, the container 3 has a base plate 4 and/orcover plate 5 and/or at least one holding device 6.

It is shown in FIGS. 1, 2, 4 to 14 that at least one part of the wall ofthe container 3 is designed flexible so that the means for transfer ofsubstance could be operated at least partially from the outside throughthe flexible wall. FIGS. 4 to 14 show that the flexible wall is presentin the form of a bellows 7.

The first practical example of a very simple design of the deviceaccording to the invention according to FIGS. 1 and 2 is based on thegravity principle in order to transfer a substance from closed sourcesystem G in the other closed system Z or G/Z. The container 3 is presentas a collapsible, flexible bag with a volume of 30 mL, which is alreadyfilled with substance and whose connector 2 faces the floor in theoperating position.

In both variants of the first practical example the connector 2 extendsslightly with one end in sealed fashion through the base plate 4 incontainer 3 into the substance and is provided there with a reclosablesnap closure 8. The snap closure 8 consists of a sealing material, isequipped with a fastening bridge 9 and can be operated through theflexible wall of the container 3. The connector 2 has a metering valve13. The connector 2 in FIG. 1 is available for sterile connection to theclosed target system Z.

The device according to the invention according to the variant depictedin FIG. 2 of the first practical example forms an overall system G+G/Z,which combines the closed systems G and G/Z connected to each other insterile fashion at the plant via connection piece 15. System G/Z of theoverall system G+G/Z essentially corresponds to the device described inFIG. 3B according to second practical example. A cross connector isdenoted 14, which symbolizes the sterile system connection betweenconnector 2 of overall system G+G/Z with the connector 2 of the targetsystem Z.

In the second practical example according to FIGS. 3A to 3E thecontainer 3 is provided as a calibrated drip chamber 12 to accommodatethe substance, which is constructed essentially of a base plate 4 and acover plate 5 and a plastic jacket extending in between. FIGS. 3A and 3Bshow a variant with two connectors 2, which include an inlet 10 and anoutlet 11 pointing toward the floor in the operating position. The inlet10 and the outlet 11 extent through the base plate 4 and the cover plate5 of the drip chamber 12 and are welded tightly in them. The pressurecompensation device 1 is also connected in sealed fashion to the coverplate 5 of drip chamber 12 and extends into it. Both connectors 2 areassigned a metering valve 13.

A device according to FIGS. 3A to 3E represents a closed source andtarget system G/Z in the sense of a gravity-operating metering device,which can be combined with different source systems G and target systemsZ and thus permit sterile and volume-precise transfer of the substance.The device is to be removed before use from a sterilized blister package16.

The components of a device according to the invention according to allpractical examples are arranged with a sterilized blister package 16before sterile connection to another closed system G, G/Z, Z, which isshown as an example in FIGS. 3A, 11A and 6. The blister packet 16 ispyrogen-free and gamma-sterilized. The blister packet 16 is alsodisinfected with 70% ethanol.

The variant depicted in FIG. 3C shows an inlet 10 connected in sterilefashion to source system G and four outlets 11, which are connected insterile fashion to the target systems Z via two connectors 2. Two of theoutlets 11 are still without function here. A metering 13 is assigned toa connector 2 on the outlet side.

Another variant of the device with four inlets 10 is shown in FIG. 3D,which are connected in sterile fashion via connectors 2 to four sourcesystems G and in which a metering valve 13 is provided for each. Amixture of four substances can be produced here in drip chamber 12. Inthe variant depicted in FIG. 3D only one outlet 11 is provided, whoseconnector 2 is connected in a sterile fashion to the target system Z andhas a metering valve 13.

Finally a fourth variant of the second practical example of the deviceaccording to the invention is shown in FIG. 1E with four inlets 10 andfour outlets 11 as well as a metering valve 13 on each connector 2. Themixture produced from the substances of source systems G can betransferred from drip chamber 12 into target systems Z.

The third practical example of the device according to the invention isdepicted in FIGS. 4 to 7 in different variants, which are also based onthe gravity principle. A receptacle 17 in the form of a bottle or ampuleis contained in the container 3 of source system G, within which thesubstance is situated and whose closure faces the floor in the operatingposition. The single connector 2 in the operating position also facesdownward. The receptacle 17 is present in FIGS. 4 and 7 as an ampule, inFIGS. 5 and 6 as a bottle. A puncture stopper 20 is provided as closure.The pressure compensation device 1 extends through base plate 4 intovessel 3 and is connected tightly and in sterile fashion. The receptacle17 is fastened to the cover plate 5 of container 1. On the outside ofcover plate 5 an eye 21 is arranged, which serves for a suspension ofthe device. A short cannula 18 serves for transfer of the substancepresent here as liquid. In addition a long cannula 19 is provided forair supply. In the operating position both cannulas 18, 19 puncture thepuncture stopper 20 of receptacle 17 and extend into it and thesubstance situated there, the long cannula ultimately extending beyondthe level of the substance. The short cannula 18 is in flow connectionwith connector 2. Special holding devices 6 are provided for thecannulas 18, 19 in the variants of the third practical example depictedin FIGS. 4 and 7 on base plate 4.

The variant of the third practical example depicted in FIG. 4 implementsa semiquantitative substance transfer and is particularly simple andcost-effective to produce. The volume of the receptacle 17, namely theampule, is predetermined and it can also be estimated how much wasremoved via the predetermined immersion depth of the short cannula 18into the ampule. On removal of the total amount the precise volume ispresent over the entire volume of the receptacle 17 and the immersiondepth of the short cannula 18. Removal of a partial amount can occur bymeans of the metering valve 13. The long cannula 19 opens into thecontainer 3 so that pressure compensation can occur via the pressurecompensation device 1 that discharges into container 3. In the devicedepicted in FIG. 4 the bellows 7 in the rest position is present in thedeployed state, is supported by a stabilizer not shown here and containsthe two cannulas 18, 19 spaced by the puncture stopper 20, which arefastened to base plate 4 or holding device 6. The short cannula 18extends with its connection piece 15 facing away from receptacle 17 intothe connector 2 in the form of a PVC tube. The operating positiondepicted in FIG. 4 shows that a stabilizer is no longer present and thatthe bellows 7 is compressed, in which case the displaced air escapesinto the pressure compensation device 1.

The device depicted in FIG. 4 is operated as follows from the outsidevia bellows 7 of the container 3:

-   -   sterile connection of connector 2 of the closed source system G        to the connector 2 of target system Z,    -   removal of a stabilizer (not shown here),    -   compression of the bellows 7 and puncturing of the puncture        stopper 20 with both cannulas 18, 19, filling of the pressure        compensation device 1 with the air displaced from container 3,    -   introduction of the substance through the short cannula 18 into        connector 2,    -   regulation of transfer of substance of source system G via        metering valve 13.

A somewhat more demanding variant of the third practical example isdepicted in FIGS. 5 and 6. There the cover plate 5 of a calibrated dripchamber 12 is integrated, namely welded into the base plate 4 of thecontainer 3 and is part of source system G. Outlet 11 and connector 2emerge from the drip chamber 12. The two cannulas 18, 19 extend into thedrip chamber 12 via connection pieces 15 and inlets 10. In addition tothe two inlets 10 cooperating with the connection pieces 15, a thirdfree inlet 10 is provided, which connects the drip chamber 12 to thecontainer 3 so that the pressure equalization device 1 of container 3 isalso responsible for pressure equalization in the drip chamber 12. Theconnection piece 15 of the short cannula 18 has a metering valve 13which can be adjusted via bellows 7. A metering valve 13 is alsoprovided on connector 2.

FIG. 6 shows a device according to FIG. 5 within blister package 16,which includes a stabilizer 22 with protective devices 23 for the twocannulas 18, 19. The stabilizer 22 is fastened to the holding device 6within blister package 16, which is shown in FIG. 5. The connectionpieces 15 of the two cannulas 18, 19 are fastened in a retaining plate24 on their end on the cannula side. When the device is brought intooperation, the retaining plate 24 with the cannulas 18, 19 is releasedvia the bellows 7 from the stabilizer 22 and the protective devices 23and the puncture stopper 20 of the receptacle 17 is punctured until theretaining plate 24 lies against it.

Another variant of the third practical example of the device accordingto the invention shows in FIGS. 7A and 7B a receptacle 17 in the form ofan ampule similar to that of FIG. 4 but with differences relative to it.

One difference is that an overall system G+G/Z is prescribed there,which consists of a source system G and a combined source/target systemG/Z as shown in FIG. 3B. Here the sterile connection is produced betweensource system G and combined source/target system G/Z at the plantthrough a connection piece 15, which is equipped with a metering valve13. The connection piece 15 of the short cannula 18 discharges in acalibrated drip chamber 12. The long cannula 19 opens into the pressurecompensation device 1 via its connection piece 15. The pressurecompensation device 1 is connected via two additional connection pieces15 to container 3 in the drip chamber 12 and therefore ensures pressurecompensation everywhere in the overall system G+G/Z. A connector 2protrudes from the overall system G+G/Z, especially from the dripchamber 12, which is connected in a sterile fashion to the connector 2on the target system Z.

Another difference is that the holding device 6 is designed in the formof a slotted sleeve, which is supported in the rest position in FIG. 7Aagainst the shoulder of the ampule and ensures spacing of the cannulas18, 19 relative to the puncture stopper 20. In the operating positionaccording to FIG. 7B the holding device 6 is pushed over the ampule, inwhich the cannulas 18, 19 puncture the puncture stopper 20.

The container 3 as in FIG. 4 is a combination of enclosure and bellows7. The latter extends in the rest position in the area of the holdingdevice 6, whereas the receptacle 17 is almost enclosed.

FIGS. 8 to 13 show a fourth practical example of the device according tothe invention in which the means for transfer of substance include acalibrated syringe with an ampule plunger 25 and an ampule barrel 26.

According to the variants of the four practical examples depicted inFIGS. 8 to 11, the syringe is arranged within the container 3 and can beoperated from the outside via its bellows 7 extending between the coverplate 5 and base plate 4. In the syringes according to FIGS. 12 and 13the container 3 is formed by a bellows 7 in the area of the ampuleplunger 25, which is connected in sealed fashion to the ampule barrel26. The end of the ampule plunger 25 facing away from the ampule barrel26 is glued to the base plate 4 of the container 3. The ampule barrel 26in all variants of the fourth practical example temporarily accommodatesthe substance.

FIGS. 8A, 8B show the arrangement of the syringe and the receptacle 17in the form of an ampule filled with substance with puncture stopper 20within container 3 by mean of matching holding devices 6, which aremolded onto the base plate 4. The receptacle 17 has a puncture stopper20 and consists here of borosilicate glass. Dimethyl sulfoxide (DMSO) iscontained in a substance in the receptacle 17. The puncture stopper 20consists of elastomer and is teflon-coated for chemical stability. Theholding devices 6 according to the two variants depicted in FIGS. 8A, 8Band 9 hold the receptacle 17, a protective device 23 for the cannula 28of the syringe, the connection piece 15 and the ampule barrel 26 withampule plunger 25.

A stabilizer 22 is provide in the container 3 according to FIG. 8A,which has the task of holding the receptacle 17 contained in container 3and the cannula 28 for the syringe (i.e., components that might loosen)in position during transport. The connector 2 and the pressurecompensation device 1 are each connected via a passage opening (notfurther shown) to the container 3, in which a sealing connection (here awelded connection) is made on the passage opening.

The device depicted in FIGS. 8A and 8B according to the variant there ofthe fourth practical example is operated as follows from the outside viabellows 7, after the sterile connection to target system Z is completed:

-   -   connection of the ampule barrel 26 of the syringe to cannula        28—here via a Luer lock connection,    -   puncturing of the puncture stopper 20 of receptacle 17 and        introduction of the cannula 28 into the substance,    -   suction of the substance into the ampule barrel 26 by extension        of the ampule plunger 25,    -   loosening of the cannula 28 and positioning in the protective        device 23 in the holding device 6,    -   as shown in FIG. 8B, connection of the ampule barrel 26 to the        connection piece 15—here via a Luer lock connection,    -   tightening of the syringe in an syringe pump 29,    -   transfer of the substance from the ampule barrel 26 into the        connection piece 15, connector 2 and finally into system Z by        introducing ampule plunger 25 into ampule barrel 26,    -   sterile disconnection of the systems G and Z after transfer.

In FIGS. 8A and 8B the connection piece 15 is present as a tubularconnection piece, in FIG. 9 as an internal line 27. In the variantdepicted in FIG. 9 the receptacle 17 is empty and the system there isinitially target system Z. Substance removal is carried out at apredetermined location via the internal line 27 connected on ampulebarrel 26, which after sterile connection to source system G throughconnectors 2 enters and is positioned in it. The following steps arecarried out when the internal line 27 is positioned in source system G:

-   -   connection of the ampule barrel 26 to the internal line 27—here        via a Luer lock connection,    -   suction of the substance from system G into the ampule barrel 26        by retracting the ampule plunger 25 and filling the syringe,    -   loosening of the internal line 27 from the ampule barrel 26,    -   connection of the ampule barrel 26 to cannula 28,    -   puncturing of the puncture stopper 20 of receptacle 17 and        introduction of the substance from the ampule barrel 26 into the        receptacle 17 by introducing the ampule plunger 25 into ampule        barrel 26,    -   removal of the cannula 28 from the receptacle 17, loosening of        the cannula 28 from the ampule barrel 26 and positioning in the        protective device 23,    -   withdrawal of the internal line 27 from system G, spiral winding        and arrangement,    -   sterile disconnection of systems G and Z after transfer,    -   reuse of the filled receptacle 17 in the clean room.

The syringe depicted in FIG. 10 is already provided at the plant with asubstance in ampule barrel 26 and has a valve 30 on its ampule barrel 26for opening and closure. This device is furnished in the filled stateand represents a source system G. Here only a single holding device 6 isprovided on the base plate 4 of container 3. The free end of the ampulebarrel 26 forms the connector 2 that passes through the base plate 4 insealed fashion. This is a disposable article that is disposed of afteremptying.

The variant of the fourth practical example of the device according tothe invention depicted in FIGS. 11A and 11G also shows a syringe, whichis already packaged with a cannula 28 on the ampule barrel 26 and has acannula closure 31. Here a specially designed container 3 is providewith two chambers 32, 33, which are connected via two connection pieces15 to the pressure compensation device 1. The first chamber 32 containsthe ampule plunger 25 of the syringe and the second chamber 33 containsthe ampule barrel 26 with the cannula 28 and the cannula closure 31. Theend of the ampule plunger 25 is firmly connected to the base plate 4 ofthe first chamber 32. The second chamber 33 of the container 3 forms theconnector 2 for sterile connection to the connector of another closedsystem G, Z on the end facing away from the first chamber 32.

The other closed system G apparent from FIGS. 11B to 11F is in the formof an ampule containing the substance, which has a plastic enclosurewith a connector 2 extending from it for sterile connection of connector2 of the container 3 and the first closed system G/Z. The ampule of theclosed system G consists of borosilicate glass and is equipped with apuncture stopper 20 made of elastomer. The device in question isoperated as follows from the outside via bellows 7 from thecorresponding chamber 32, 33 of container 1:

-   -   removal of the device from the blister package 16 shown in FIG.        11A,    -   sterile connection of connector 2 of the closed system G/Z with        connector 2 of the enclosed ampule of the closed system G and        removal of the cannula closure 31 in FIG. 11B,    -   in FIG. 11C: puncture of the puncture stopper 20 of the ampule        of system G, introduction of cannula 28 into the ampule of        system G,    -   in FIG. 11D: introduction of the ampule plunger 25 into ampule        barrel 26 and introduction of air from the ampule barrel 26 into        the ampule of system G containing the substance, in which case        an overpressure is formed there so that fine metering of the        substance is made possible during removal without a vacuum        effect; on size reduction of chambers 32, 33 the pressure        compensation device 1 is filled with air from chambers 32, 33,    -   in FIG. 11E: beginning of suction of the substance from system G        into the ampule barrel 26 by filling of the ampule plunger 25        from the ampule barrel 26, in which the system G/Z has a target        function; on increasing size of chambers 32, 33 air enters them        from the pressure compensation device 1,    -   in FIG. 11F: suction of substance from system G into the ampule        barrel 26 is completed, sterile disconnection of connector 2 of        the closed system G/Z from the connector 2 of system G occurs,    -   in FIG. 11G: readiness for sterile connection with another        closed system Z in order to transfer the substance transferred        from system G/Z, which now has a source function, into system Z.

In the other variant of the fourth practical example of the deviceaccording to the invention depicted in FIGS. 12A to 12D the ampuleplunger 25 is in flow connection with the ampule barrel 26. The ampuleplunger 25 is connected via a connector 2 in sterile fashion to a sourcesystem G. This connector 2 extends as an inner tube into ampule plunger25 and opens centrally in the free end of ampule plunger 25 into ampulebarrel 26. The connector 2 on the side of the ampule plunger is equippedwith a metering valve 13. A connector 2 is formed from the ampule barrel26, which is connected in sterile fashion to a closed system Z andincludes a metering valve 13.

For suction of substance from source system G the connector 2 on theampule barrel 26 is closed, the one on ampule plunger 25 is opened andthe latter moved out form the ampule barrel 26. The substance then flowsfrom source system G into ampule barrel 26. The specially designedsyringe here is a combination of source and target system G/Z. Duringfilling the target function comes into play, during transfer to targetsystem Z the source function does. To convey the substance drawn fromsystem G into system G/Z into the target system Z the metering valve 13is closed on the side of the ampule plunger and opened on the side ofthe ampule barrel. The ampule plunger 25 is introduced to the ampulebarrel 26 and thus transfers the substance to system Z.

The connector 2 emerging from the ampule barrel 26 in FIG. 12D isconnected in sterile fashion to a closed system Z with an internal line27. Internal line 27 is manipulated via the bellows 7 of container 3 andintroduced to a next closed system G/Z in order to position thesubstance there precisely.

An overall system G+G/Z consisting of a closed source system G with thefeatures of the source system according to FIGS. 7A, 7B and a closedsystem G/Z with the features shown in FIGS. 12A to 12D, including thesource and target function, is shown in FIGS. 13A to 13D. In thisvariant, in which the third and fourth practical examples overlap, eachsystem G and G/Z within the overall system G+G/Z has its own pressurecompensation device 1 with connection pieces 15. With reference tosystem G the pressure compensation device 1 is in flow connection withcontainer 3 and the long cannula 19. With reference to system G/Z thepressure compensation device 1 is also in flow connection with thecontainer 3 there. Sterile connection of the two systems G and G/Z tothe overall system G+G/Z is produced at the plant via the connectionpiece 15 that extends into the ampule plunger 25 up to its tip. Thesubstance is drawn into the ampule barrel 26 via the small cannula 18connected to the connection piece 15 from receptacle 17 and finally fromthere transferred to the target system Z. FIG. 13A shows the restposition in which the cannulas 18, 19 are still fastened in the holdingdevice 6. The puncture stopper is already punctured in FIG. 13B, thebellows 7 of container 3 of the source system G is collapsed and thepressure compensation device 1 is filled with displaced air. Themetering valve 13 on the connection piece 15 is opened in FIG. 13C andthe ampule plunger 25 of the syringe filled, in which case the pressurecompensation device 1 now contains less air and the volume of thebellows 7 is increased. The substance of the source system G flows intothe ampule barrel 26 according to the drawn arrows. In FIG. 13D thesuction process is completed. The ampule plunger 25 transfers thesubstance according to the drawn arrows from the ampule barrel 26 intoconnector 2 and finally to the target system Z. During this transfer themetering valve 13 is closed on the side of the ampule plunger and openedon the side of the ampule barrel.

A fifth practical example of the device according to the inventionaccording to FIG. 14 deals with a calibrated carpule as means fortransfer of substance with a carpule plunger 34 and a carpule barrel 35in which the substance is contained. The carpule barrel 35 is closedwith puncture stopper 20. The transparent container 3 contained in thecarpule includes two chambers 32, 33. Each chamber 32, 33 is in flowconnection with a pressure compensation device 1. The first chamber 32includes a cannula 36, which faces with its tip the puncture stopper 20of the carpule barrel 35 and with its opposite end formed as aconnection piece 15 extends into the connector 2.

A sliding stopper 37 is movable over the carpule plunger 34. The carpuleplunger 34 is arranged in the second chamber 33, which includes abellows 7 and a cylindrical section in the form of a stable sleeve 38.The end of the carpule plunger 34 is glued to the cover plate 5 on whichthe bellows 7 is arranged. The bellows 7 then grades into the stablesleeve 38, which also accommodates the carpule barrel 35. An annularshoulder 40 facing radially inward is provided on the end of the sleeve38 on the carpule barrel side, against which the carpule barrel 35 issupported. The sleeve 38 on the end of the carpule barrel 35 on theplunger side also has an annular shoulder 41 facing radially inward,which counteracts an axial movement of the carpule plunger 35. While theannular shoulder 40 is already molded onto sleeve 38, the annularshoulder 41 is formed by introducing a ring into sleeve 38 afterintroduction of the carpule barrel 35 into sleeve 38, which is welded tosleeve 38 and thus forms the annular shoulder 41.

The first chamber 32 is welded onto the annular shoulder 40 of sleeve38. The chambers 32, 33 are in flow connection to the slightest degreebut not sufficient to use only one pressure compensation device 1. Inaddition, the first chamber 32 has a coupling tube 39 and in it abellows 7 welded onto the base plate 4. The coupling tube 39 overlapsthe free end of the stable sleeve 38, both components are movablerelative to each other and contain snap-in devices in the form of arecess 42 and protrusion 43 which engage in the operating position andfix the position of cannula 36 in carpule barrel 35.

The device present as a source system G already filled at the plant withsubstance according to the fifth practical example is operated asfollows:

-   -   sterile connection of connector 2 of the closed system G to the        connector 2 also present as a plastic tube of the closed system        Z,    -   movement of the coupling tube 39 with bellows 7 and the cannula        36 of the first chamber 32 welded onto the base plate 4 onto the        stable sleeve 38 of the second chamber 33 up to recess 40, in        which case the cannula 36 punctures the puncture stopper 20 of        the carpule barrel 35 filled with substance and is immersed in        the substance and the protrusion 41 snaps into recess 40; the        pressure compensation device 1 there is filled with air through        the volume reduction of the first chamber 32,    -   the bellows 7 of the second chamber 33 and the carpule plunger        34 are moved to the sliding stopper 37 and in this case the        pressure compensation device 1 there is filled with air through        the volume reduction of the second chamber 33,    -   the sliding stopper 37 is pushed in the carpule barrel 35 in the        direction of cannula 36 and substance displaced into cannula 36        and the desired amount of substance transferred to receptacle        system Z;    -   after substance transfer in the desired amount sterile        disconnection of connector 2 of the closed system G occurs form        the connector 2 of system Z.

FIGS. 3A, 6 and 11A show that the components of the device according tothe invention with a closed system G or G/Z are arranged within asterile package, namely a blister package 16 before sterile connectionto the other closed system Z and/or G. The package has a smooth surfacewithout recesses, to which a disinfectant, especially 70% ethanol, isapplied, since this is introduced to a clean room.

With respect to further features not shown in the figures, the generalpart of the description is referred to. Finally, it is pointed out thatthe instructions according to the invention are not restricted to thepractical examples just explained.

LIST OF REFERENCE NUMBERS

-   1 Pressure compensation device-   2 Connector-   3 Container-   4 Base plate-   5 Cover plate-   6 Holding device-   7 Bellows-   8 Snap closure-   9 Fastening bridge-   10 Inlet-   11 Outlet-   12 Calibrated drip chamber-   13 Metering valve-   14 Cross connector/system connection-   15 Connection piece-   16 Blister package-   17 Receptacle-   18 Short cannula-   19 Long cannula-   20 Puncture stopper-   21 Eye-   22 Stabilizer-   23 Protective device-   24 Holding plate-   25 Ampule plunger-   26 Ampule barrel-   27 Internal line-   28 cannula-   29 Syringe pump-   30 Valve-   31 Cannula closure-   32 First chamber-   33 Second chamber-   34 Carpule plunger-   35 Carpule barrel-   36 Cannula-   37 Sliding stopper-   38 Cylindrical section, sleeve-   39 Coupling tube-   40 Annular shoulder-   41 Annular shoulder-   42 Recess-   43 Protrusion-   G closed system/source system-   Z closed system/target system-   G/Z closed system with source and target function-   G+G/Z overall system consisting of G and G/Z

1.-58. (canceled)
 59. A method for transfer of a substance betweenclosed systems, said method comprising: providing closed systems, namelyat least one source system and at least one target system, which aresimply connected in sterile fashion before transfer, in which thesubstance reaches the target system and in which after transfer of thesubstance the target system and the source system can be separated fromeach other in sterile fashion, wherein pressure differences occurringduring transfer of the substance are compensated within the system. 60.The method according to claim 59, wherein pressure compensation occurswhere volume changes of the substance occur.
 61. The method according toclaim 59, wherein the substance is transferred in metered fashion. 62.The method according to claim 59, wherein the substance is transferredactive from the source system, especially by a calibrated syringe orcarpule, to the target system or wherein the substance is activelyremoved from the source system, especially by a calibrated syringe orthat the substance reaches the target system under the influence ofgravity.
 63. The method according to claim 59, wherein the source systemis connected in sterile fashion to several other source systems.
 64. Themethod according to claim 59, wherein the target system becomes thesource system when the received substance is conveyed to another targetsystem.
 65. The method according to claim 59, wherein the substance isintroduced to the source system in sterile fashion under cleanroomconditions, which is closed in sterile fashion.
 66. A device fortransfer of a substance between closed systems, said device comprising:closed systems configured to be connected in sterile fashion to eachother and configured to be separated in sterile fashion from each otherand which have means for transfer of the substance, wherein a pressurecompensation device is provided, which is in flow connection in sterilefashion to at least one system.
 67. The device according to claim 66,wherein the pressure compensation device is bonded to one system. 68.The device according to claim 66, wherein the means for transferincludes at least one connector for sterile connection to at least oneadditional system.
 69. The device according to claim 68, wherein acontainer is provided and wherein the connector is bonded in sterilefashion to the container of system.
 70. The device according to claim69, wherein the container includes a base plate or a cover plate or atleast one holding device.
 71. The device according to claim 69, whereinat least part of the wall of the container is designed flexible so thatmeans to transfer the substance can be operated at least partially fromoutside via the flexible wall, especially via a bellows.
 72. The deviceaccording to claim 66, wherein one system is a component of an overallsystem and a sterile connection also exists within the overall system.73. The device according to claim 69, wherein the substance can betransferred from one system, especially under the influence of gravity,into the other closed system, the connector facing the floor in theoperating position.
 74. The device according to claim 73, wherein theconnector of one system with one end opens into the container andpreferably extends minimally into the substance and has a snap-inclosure of sealing material with a fastening bridge which can beoperated via the flexible wall of the container.
 75. The deviceaccording to claim 73, wherein the container has a preferablycollapsible bed with a volume between 30 mL and 1000 mL or 10 mL to 30mL.
 76. The device according to claim 66, wherein at least twoconnectors are provided, which include an inlet and an outlet facing thefloor in the operating position.
 77. The device according to claim 76,wherein a calibrated drip chamber is provided as container, in which thesubstance is at least temporarily contained.
 78. The device according toclaim 77, wherein the calibrated drip chamber forms a closed system withconnectors in the sense of a gravity-operated metering device and isboth source and target system.
 79. The device according to claim 77,wherein the inlet and the outlet open in sealed fashion into the dripchamber.
 80. The device according to claim 76, wherein a metering deviceis assigned to the connector.
 81. The device according to claim 69,wherein a receptacle is contained in the container of the system in theform of a bottle or ampule within which the substance is situated andwhose closure faces the floor in the operating position.
 82. The deviceaccording to claim 81, wherein the means for transfer of the substanceincludes a short cannula for transfer of the substance, especially aliquid, and a long cannula for air or inert gas supply, in which thecannulas puncture the closure of the receptacle in the operatingposition and extend into the receptacle and in which the short cannulais in flow connection with the connection.
 83. The device according toclaim 82, wherein the long cannula opens into the container.
 84. Thedevice according to claim 82, wherein the short cannula and the longcannula in the rest position are arranged in a holding device in theform of a slotted sleeve, which is supported on one side against thebase plate of the container, and against the receptacle on the otherside and which encloses the receptacle in the operating position,whereas the cannulas puncture the closure of the receptacle.
 85. Thedevice according to claim 82, wherein the volume of the receptacle ispredetermined so that the amount removed can be estimated and theclosure preferably includes a metering valve.
 86. The device accordingto claim 81, wherein the container includes a calibrated drip chamberinto which at least a short cannula extends via a connection piece andon which the connection facing the floor in the operating position isprovided.
 87. The device according to claim 86, wherein the long cannulaopens into the pressure compensation device, which ensures pressurecompensation in container and in the receptacle as well as thecalibrated drip chamber of the overall system.
 88. The device accordingto claim 66, wherein the means to transfer substance includes at leastone calibrated syringe with an ampule plunger and an ampule barrel. 89.The device according to claim 88, wherein the syringe is arranged withina container and can be operated from the outside via an at leastpartially flexible wall of the container especially via a bellows. 90.The device according to claim 88, wherein the ampule barrelsimultaneously forms an at least temporary receptacle for the substance.91. The device according to claim 88, wherein the system has anoverlapping source and target function if filling with substance andrelease of substance occur in the same system.
 92. The device accordingto claim 88, wherein a connection piece in flow connection with theconnector is provided for connection to the syringe within thecontainer.
 93. The device according to claim 92, wherein the connectionpiece is present in the form of an internal line.
 94. The deviceaccording to claim 90, wherein a receptacle with substance in the formof an ampule with a puncture stopper is provided in the container. 95.The device according to claim 88, wherein the ampule barrel includes acannula with a cannula closure, which can be manipulated from theoutside via the flexible wall of the container.
 96. The device accordingto claim 95, wherein the container includes two chambers, both of whichare in flow connection with the pressure compensation device.
 97. Thedevice according to claim 96, wherein the first chamber contains theampule plunger and wherein the second chamber contains the ampule barrelwith the cannula.
 98. The device according to claim 96, wherein thesecond chamber of the container forms the connector for sterileconnection to the connector of the source system or the connector of thetarget system on the end facing away from the first chamber.
 99. Thedevice according to claim 88, wherein the system has a container in theform of a plastic enclosure and that an ampule containing the substanceis arranged within the plastic enclosure with a puncture stopper made ofelastomer.
 100. The device according to claim 88, wherein the ampuleplunger is in flow connection with the ampule barrel.
 101. The deviceaccording to claim 100, wherein the ampule plunger can be connected insterile fashion to a closed system via a connector equipped with ametering valve and wherein the connection extends into the ampuleplunger and opens from there into the ampule barrel.
 102. The deviceaccording to claim 101, wherein the ampule barrel has a connector forsterile connection to a closed system equipped with a metering valvefacing away from the ampule plunger.
 103. The device according to claim102, wherein for suction of substance from the closed system themetering valve adjacent to the ampule barrel is closed and the meteringvalve adjacent to the ampule plunger is opened.
 104. The deviceaccording to claim 103, wherein for transfer of the substance drawn intothe ampule barrel to the target system the metering valve adjacent tothe ampule barrel is opened and the metering valve adjacent to theampule plunger is closed.
 105. The device according to claim 100,wherein the container includes a bellows in the area of the ampuleplunger and wherein the bellows is connected in sealed fashion to theampule barrel.
 106. The device according to claim 100, wherein theclosed system includes a short cannula for transfer of the substance,especially a liquid, and a long cannula for air or inert gas supply, inwhich the cannulas puncture the closure of the receptacle in theoperating position and extend into the receptacle and in which the shortcannula is in flow connection with the connection, and wherein the longcannula opens into the container.
 107. The device according to claim106, wherein the source system is in sterile connection with the ampuleplunger via a connection piece of the short cannula and wherein thesource system and the closed system comprising the syringe form anoverall system.
 108. The device according to claim 88, wherein thesyringe can be tightened in a syringe pump so the transfer of substancecan be accomplished automatically at pre-established times or over adetermined period with precise volume.
 109. The device according toclaim 66, wherein the means for transfer of substance includes a carpulewith a carpule plunger and a carpule barrel containing the substance.110. The device according to claim 109, wherein the container includestwo chambers.
 111. The device according to claim 110, wherein the firstchamber includes a cannula, which faces the carpule barrel with its tipand extends into the connector with its opposite end.
 112. The deviceaccording to claim 110, wherein the second chamber comprises acylindrical section and a bellows, in which the carpule barrel iscontained within the cylindrical section as well as part of the carpuleplunger and in which the rest of the carpule plunger is contained withinthe bellows.
 113. The device according to claim 110, wherein the secondchamber and a coupling tube of the first chamber are movable relative toeach other and can preferably be fastened to each other in apredetermined position.
 114. The device according to claim 66, whereinthe connection is connected in sterile fashion to a closed system, whichcontains an internal line and wherein the system containing the internalline transfers the substance to the next closed system.
 115. The deviceaccording to claim 66, wherein the components of the device or theclosed system are arranged within a sterile package before sterileconnection to the other closed system.
 116. The device according toclaim 115, wherein the package has a smooth surface on which adisinfectant, especially 70% ethanol, can be applied.